Ambient air pollution and maternal cardiovascular health in pregnancy.

In this review, we summarise the current epidemiological and experimental evidence on the association of ambient (outdoor) air pollution exposure and maternal cardiovascular health during pregnancy. This topic is of utmost clinical and public health importance as pregnant women represent a potentially susceptible group due to the delicate balance of the feto-placental circulation, rapid fetal development and tremendous physiological adaptations to the maternal cardiorespiratory system during pregnancy.Several meta-analyses including up to 4 245 170 participants provide robust evidence that air pollutants, including particulate matter, nitrogen oxides and others, have adverse effects on the development of hypertensive disorders of pregnancy, gestational diabetes mellitus and cardiovascular events during labour. Potential underlying biological mechanisms include oxidative stress with subsequent endothelial dysfunction and vascular inflammation, ß-cell dysfunction and epigenetic changes. Endothelial dysfunction can lead to hypertension by impairing vasodilatation and promoting vasoconstriction. Air pollution and the consequent oxidative stress can additionally accelerate ß-cell dysfunction, which in turn triggers insulin resistance leading to gestational diabetes mellitus. Epigenetic changes in placental and mitochondrial DNA following air pollution exposures can lead to altered gene expression and contribute to placental dysfunction and induction of hypertensive disorders of pregnancy.The maternal and fetal consequences of such cardiovascular and cardiometabolic disease during pregnancy can be serious and long lasting, including preterm birth, increased risk of type 2 diabetes mellitus or cardiovascular disease later in life. Acceleration of efforts to reduce air pollution is therefore urgently needed to realise the full health benefits for pregnant mothers and their children.

An interoperability framework for multicentric breath metabolomic studies.

Exhaled breath contains valuable information at the molecular level and offers promising potential for precision medicine. However, few breath tests transition to routine clinical practice, partly because of the missing validation in multicenter trials. Therefore, we developed and applied an interoperability framework for standardized multicenter data acquisition and processing for breath analysis with secondary electrospray ionization-high resolution mass spectrometry. We aimed to determine the technical variability and metabolic coverage. Comparison of multicenter data revealed a technical variability of ∼20% and a core signature of the human exhaled metabolome consisting of ∼850 features, corresponding mainly to amino acid, xenobiotic, and carbohydrate metabolic pathways. In addition, we found high inter-subject variability for certain metabolic classes (e.g., amino acids and fatty acids), whereas other regions such as the TCA cycle were relatively stable across subjects. The interoperability framework and overview of metabolic coverage presented here will pave the way for future large-scale multicenter trials.

Pollen exposure is associated with risk of respiratory symptoms during the first year of life.

BACKGROUND: Pollen exposure is associated with respiratory symptoms in children and adults. However, the association of pollen exposure with respiratory symptoms during infancy, a particularly vulnerable period, remains unclear. We examined whether pollen exposure is associated with respiratory symptoms in infants and whether maternal atopy, infant's sex or air pollution modifies this association. METHODS: We investigated 14,874 observations from 401 healthy infants of a prospective birth cohort. The association between pollen exposure and respiratory symptoms, assessed in weekly telephone interviews, was evaluated using generalized additive mixed models (GAMMs). Effect modification by maternal atopy, infant's sex, and air pollution (NO2 , PM2.5 ) was assessed with interaction terms. RESULTS: Per infant, 37 ± 2 (mean ± SD) respiratory symptom scores were assessed during the analysis period (January through September). Pollen exposure was associated with increased respiratory symptoms during the daytime (RR [95% CI] per 10% pollen/m3 : combined 1.006 [1.002, 1.009]; tree 1.005 [1.002, 1.008]; grass 1.009 [1.000, 1.23]) and nighttime (combined 1.003 [0.999, 1.007]; tree 1.003 [0.999, 1.007]; grass 1.014 [1.004, 1.024]). While there was no effect modification by maternal atopy and infant's sex, a complex crossover interaction between combined pollen and PM2.5 was found (p-value 0.003). CONCLUSION: Even as early as during the first year of life, pollen exposure was associated with an increased risk of respiratory symptoms, independent of maternal atopy and infant's sex. Because infancy is a particularly vulnerable period for lung development, the identified adverse effect of pollen exposure may be relevant for the evolvement of chronic childhood asthma.

Increased Impact of Air Pollution on Lung Function in Preterm versus Term Infants: The BILD Study.

Rationale: Infants born prematurely have impaired capacity to deal with oxidative stress shortly after birth. Objectives: We hypothesize that the relative impact of exposure to air pollution on lung function is higher in preterm than in term infants. Methods: In the prospective BILD (Basel-Bern Infant Lung Development) birth cohort of 254 preterm and 517 term infants, we investigated associations of particulate matter ⩽10 µm in aerodynamic diameter (PM10) and nitrogen dioxide with lung function at 44 weeks' postconceptional age and exhaled markers of inflammation and oxidative stress response (fractional exhaled nitric oxide [FeNO]) in an explorative hypothesis-driven study design. Multilevel mixed-effects models were used and adjusted for known confounders. Measurements and Main Results: Significant associations of PM10 during the second trimester of pregnancy with lung function and FeNO were found in term and preterm infants. Importantly, we observed stronger positive associations in preterm infants (born 32-36 wk), with an increase of 184.9 (95% confidence interval [CI], 79.1-290.7) ml/min [Formula: see text]e per 10-µg/m3 increase in PM10, than in term infants (75.3; 95% CI, 19.7-130.8 ml/min) (pprematurity × PM10 interaction = 0.04, after multiple comparison adjustment padj = 0.09). Associations of PM10 and FeNO differed between moderate to late preterm (3.4; 95% CI, -0.1 to 6.8 ppb) and term (-0.3; 95% CI, -1.5 to 0.9 ppb) infants, and the interaction with prematurity was significant (pprematurity × PM10 interaction = 0.006, padj = 0.036). Conclusions: Preterm infants showed significantly higher susceptibility even to low to moderate prenatal air pollution exposure than term infants, leading to increased impairment of postnatal lung function. FeNO results further elucidate differences in inflammatory/oxidative stress response when comparing preterm infants with term infants.

Combination of Exhaled Breath Analysis with Parallel Lung Function and FeNO Measurements in Infants.

Breath analysis by secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) offers the possibility to measure comprehensive metabolic profiles. The technology is currently being deployed in several clinical settings in Switzerland and China. However, patients are required to exhale directly into the device located in a dedicated room. Consequently, clinical implementation in patients incapable of performing necessary exhalation maneuvers (e.g., infants) or immobile (e.g., too weak, elderly, or in intensive care) remains a challenge. The aim of this study was to develop a method to extend such breath analysis capabilities to this subpopulation of patients by collecting breath samples remotely (offline) and promptly (within 10 min) transfer them to SESI-HRMS for chemical analysis. We initially assessed the method in adults by comparing breath mass spectra collected offline with Nalophan bags against spectra of breath samples collected in real time. In total, 13 adults provided 176 pairs of real-time and offline measurements. Lin's concordance correlation coefficient (CCC) was used to estimate the agreement between offline and real-time analyses. Here, 1249 mass spectral features (55% of total detected) exhibited Lin's CCC > 0.6. Subsequently, the method was successfully deployed to analyze breath samples from infants (n = 16), obtaining as a result SESI-HRMS breath profiles. To demonstrate the clinical feasibility of the method, we measured in parallel other clinical variables: (i) lung function, which characterizes the breathing patterns, and (ii) nitric oxide, which is a surrogate marker of airway inflammation. As a showcase, we focused our analysis on the exhaled oxidative stress marker 4-hydroxynonenal and its association with nitric oxide and minute ventilation.

Associations of air pollution and greenness with the nasal microbiota of healthy infants: A longitudinal study.

BACKGROUND: Air pollution and greenness are associated with short- and long-term respiratory health in children but the underlying mechanisms are only scarcely investigated. The nasal microbiota during the first year of life has been shown to be associated with respiratory tract infections and asthma development. Thus, an interplay between greenness, air pollution and the early nasal microbiota may contribute to short- and long-term respiratory health. We aimed to examine associations between fine particulate matter (PM2.5), nitrogen dioxide (NO2) and greenness with the nasal microbiota of healthy infants during the first year of life in a European context with low-to-moderate air pollution levels. METHODS: Microbiota characterization was performed using 16 S rRNA pyrosequencing of 846 nasal swabs collected fortnightly from 47 healthy infants of the prospective Basel-Bern Infant Lung Development (BILD) cohort. We investigated the association of satellite-based greenness and an 8-day-average exposure to air pollution (PM2.5, NO2) with the nasal microbiota during the first year of life. Exposures were individually estimated with novel spatial-temporal models incorporating satellite data. Generalized additive mixed models adjusted for known confounders and considering the autoregressive correlation structure of the data were used for analysis. RESULTS: Mean (SD) PM2.5 level was 17.1 (3.8 µg/m3) and mean (SD) NO2 level was 19.7 (7.9 µg/m3). Increased PM2.5 and increased NO2 were associated with reduced within-subject Ruzicka dissimilarity (PM2.5: per 1 µg/m3 -0.004, 95% CI -0.008, -0.001; NO2: per 1 µg/m3 -0.004, 95% CI -0.007, -0.001). Whole microbial community comparison with nonmetric multidimensional scaling revealed distinct microbiota profiles for different PM2.5 exposure levels. Increased NO2 was additionally associated with reduced abundance of Corynebacteriaceae (per 1 µg/m3: -0.027, 95% CI -0.053, -0.001). No associations were found between greenness and the nasal microbiota. CONCLUSION: Air pollution was associated with Ruzicka dissimilarity and relative abundance of Corynebacteriaceae. This suggests that even low-to-moderate exposure to air pollution may impact the nasal microbiota during the first year of life. Our results will be useful for future studies assessing the clinical relevance of air-pollution-induced alterations of the nasal microbiota with subsequent respiratory disease development.

Effect of breastfeeding duration on lung function, respiratory symptoms and allergic diseases in school-age children.

BACKGROUND: A positive effect of breastfeeding on lung function has been demonstrated in cohorts of children with asthma or risk for asthma. We assessed the impact of breastfeeding on lung function and symptoms at the age of 6 years in an unselected, healthy birth cohort. METHODS: We prospectively studied healthy term infants from the Bern-Basel Infant Lung Development (BILD) cohort from birth up to 6 years. Any breastfeeding was assessed by weekly phone calls during the first year of life. Risk factors (eg, smoking exposure, parental history of allergic conditions, and education) were obtained using standardized questionnaires. The primary outcomes were lung function parameters measured at 6 years of age by spirometry forced expiratory volume in 1 second, body plethysmography (functional residual capacity [FRCpleth ], the total lung capacity [TLCpleth ], and the effective respiratory airway resistance [Reff ]) and fractional exhaled nitric oxide (FeNO). Secondary outcomes included ever wheeze (between birth and 6 years), wheeze in the past 12 months, asthma, presence of allergic conditions, atopic dermatitis, rhinitis, and positive skin prick test at the age of 6 years. RESULTS: In 377 children the mean breastfeeding duration was 36 weeks (SD 14.4). We found no association of breastfeeding duration with obstructive or restrictive lung function and FeNO. After adjustment for confounders, we found no associations of breastfeeding duration with respiratory symptoms or the presence of allergic conditions. CONCLUSION: This study found no evidence of an association between breastfeeding and comprehensive lung function in unselected healthy children with long-term breastfeeding. Our findings do not support the hypothesis that the duration of breastfeeding has a direct impact on lung function in a healthy population with low asthmatic risk.

Correction to: Lung functional development and asthma trajectories.

The original version of this article unfortunately contained a mistake. The given names and family names of all authors were switched in the original publication.

Lung functional development and asthma trajectories.

Early life environmental risk factors are associated with chronic respiratory morbidity in child- and adulthood. A possible mechanism for this sustained effect is their influence on early life lung functional growth and development, a susceptible phase of rapid lung growth with increased plasticity. We summarize evidence of hereditary and environmental ante-, peri-, and early postnatal factors on lung functional development, such as air pollution, tobacco exposure, nutrition, intrauterine growth retardation, prematurity, early life infections, microbiome, and allergies and their effect on lung functional trajectories. While some of the factors (e.g., prematurity) directly impair lung growth, the influence of many environmental factors is mediated through inflammatory processes (e.g., recurrent infections or oxidative stress). The timing and nature of these influences and their impact result in degrees of impaired maximal lung functional capacity in early adulthood; and they potentially impact future long-term respiratory morbidity such as chronic asthma or chronic obstructive airway disease (COPD). We discuss possibilities to prevent or modify such early abnormal lung functional growth trajectories and the need for future studies and prevention programs.

Standardization procedures for real-time breath analysis by secondary electrospray ionization high-resolution mass spectrometry.

Despite the attractiveness of breath analysis as a non-invasive means to retrieve relevant metabolic information, its introduction into routine clinical practice remains a challenge. Among all the different analytical techniques available to interrogate exhaled breath, secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS) offers a number of advantages (e.g., real-time, yet wide, metabolome coverage) that makes it ideal for untargeted and targeted studies. However, so far, SESI-HRMS has relied mostly on lab-built prototypes, making it difficult to standardize breath sampling and subsequent analysis, hence preventing further developments such as multi-center clinical studies. To address this issue, we present here a number of new developments. In particular, we have characterized a new SESI interface featuring real-time readout of critical exhalation parameters such as CO2, exhalation flow rate, and exhaled volume. Four healthy subjects provided breath specimens over a period of 1 month to characterize the stability of the SESI-HRMS system. A first assessment of the repeatability of the system using a gas standard revealed a coefficient of variation (CV) of 2.9%. Three classes of aldehydes, namely 4-hydroxy-2-alkenals, 2-alkenals and 4-hydroxy-2,6-alkedienals-hypothesized to be markers of oxidative stress-were chosen as representative metabolites of interest to evaluate the repeatability and reproducibility of this breath analysis analytical platform. Median and interquartile ranges (IQRs) of CVs for CO2, exhalation flow rate, and exhaled volume were 3.2% (1.5%), 3.1% (1.9%), and 5.0% (4.6%), respectively. Despite the high repeatability observed for these parameters, we observed a systematic decay in the signal during repeated measurements for the shorter fatty aldehydes, which eventually reached a steady state after three/four repeated exhalations. In contrast, longer fatty aldehydes showed a steady behavior, independent of the number of repeated exhalation maneuvers. We hypothesize that this highly molecule-specific and individual-independent behavior may be explained by the fact that shorter aldehydes (with higher estimated blood-to-air partition coefficients; approaching 100) mainly get exchanged in the airways of the respiratory system, whereas the longer aldehydes (with smaller estimated blood-to-air partition coefficients; approaching 10) are thought to exchange mostly in the alveoli. Exclusion of the first three exhalations from the analysis led to a median CV (IQR) of 6.7 % (5.5 %) for the said classes of aldehydes. We found that such intra-subject variability is in general much lower than inter-subject variability (median relative differences between subjects 48.2%), suggesting that the system is suitable to capture such differences. No batch effect due to sampling date was observed, overall suggesting that the intra-subject variability measured for these series of aldehydes was biological rather than technical. High correlations found among the series of aldehydes support this notion. Finally, recommendations for breath sampling and analysis for SESI-HRMS users are provided with the aim of harmonizing procedures and improving future inter-laboratory comparisons. Graphical abstract.

Exposure to moderate air pollution and associations with lung function at school-age: A birth cohort study.

BACKGROUND: Adverse effects of higher air pollution levels before and after birth on subsequent lung function are often reported in the literature. We assessed whether low-to-moderate levels of air pollution during preschool-age impact upon lung function at school-age. METHODS: In a prospective birth cohort of 304 healthy term-born infants, 232 (79%) completed lung function at follow-up at six years. Using spatial-temporal models, levels of individual air pollution (nitrogen dioxide (NO2) and ozone (O3), particulate matter with a diameter <10 µm (PM10)) were estimated for the time windows pregnancy, first up to the sixth year of life separately, and birth until follow-up at six years. Time window means were compared to World Health Organization (WHO) guideline limits. Associations of exposure windows with spirometry and body plethysmography indices were analyzed using regression models, adjusting for potential confounders. For subgroup analysis, air pollution exposure was categorized into quartiles (four groups of 52 children). RESULTS: Mean NO2 level from birth until follow-up was [mean (range)] [11.8 (4.9 to 35.9 µg/m3)], which is almost 4-times lower than the WHO suggested limit of 40 µg/m3. In the whole population, increased air pollution levels from birth until follow-up were associated with reduced lung function at six years. In the subgroup analysis, the 52 children exposed to NO2 levels from the highest quartile during pregnancy, the first and second years of life and from birth until follow-up, had a significant decrease in forced expiratory volume in 1 s (FEV1). Per interquartile range increase of NO2, FEV1 decreased by [z-score change (95% confidence interval)] [-1.07 (-1.67 to -0.47)], [-1.02 (-1.66 to -0.39)], [-0.51 (-0.86 to -0.17)] and [-0.80 (-1.33 to -0.27)], respectively. Air pollution exposure during pregnancy and childhood resulted in a non-significant decrease in lung volume at six years, as assessed by functional residual capacity measured by body plethysmography (FRCpleth). CONCLUSION: Our results suggest that exposure to higher NO2 levels, which are still much lower than WHO guideline limits, especially during the sensitive period of early lung development, may be associated with reduced lung function at school-age. These findings support the concept of age and dose-dependent pollution effects on lung function in healthy school-aged children and underline the importance of pollution reduction measures.